Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.
Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Cell Death Dis. 2024 Oct 29;15(10):784. doi: 10.1038/s41419-024-07173-9.
Skeletal muscle mesenchymal progenitors (MPs) play a critical role in supporting muscle regeneration. However, under pathological conditions, they contribute to intramuscular adipose tissue accumulation, involved in muscle diseases, including muscular dystrophy and sarcopenia, age-related muscular atrophy. How MP fate is determined in these different contexts remains unelucidated. Here, we report that Ror2, a non-canonical Wnt signaling receptor, is selectively expressed in MPs and regulates their pathological features in a differential ligand-dependent manner. We identified Wnt11 and Wnt5b as ligands of Ror2. In vitro, Wnt11 inhibited MP senescence, which is required for normal muscle regeneration, and Wnt5b promoted MP proliferation. We further found that both Wnts are abundant in degenerating muscle and synergistically stimulate Ror2, leading to unwanted MP proliferation and eventually intramuscular adipose tissue accumulation. These findings provide evidence that Ror2-mediated signaling elicited by differential Wnts plays a critical role in determining the pathological fate of MPs.
骨骼肌间充质祖细胞（MPs）在支持肌肉再生方面发挥着关键作用。然而，在病理条件下，它们有助于肌内脂肪组织的积累，与肌肉疾病有关，包括肌肉营养不良和肌肉减少症、与年龄相关的肌肉萎缩。MP 命运在这些不同的情况下是如何决定的仍不清楚。在这里，我们报告说，Ror2，一种非经典的 Wnt 信号受体，选择性地在 MPs 中表达，并以差异配体依赖的方式调节它们的病理特征。我们鉴定出 Wnt11 和 Wnt5b 是 Ror2 的配体。在体外，Wnt11 抑制了 MP 的衰老，这是正常肌肉再生所必需的，而 Wnt5b 促进了 MP 的增殖。我们进一步发现，这两种 Wnt 在退化的肌肉中都很丰富，并协同刺激 Ror2，导致不必要的 MP 增殖，最终导致肌内脂肪组织的积累。这些发现为 Ror2 介导的信号转导由差异 Wnt 引发在决定 MPs 的病理命运方面起着关键作用提供了证据。
